Cell Interactions in the Inflamed Intestinal Mucosa

发炎肠粘膜中的细胞相互作用

• 批准号: 7917926
• 负责人: CLAUDIO FIOCCHI
• 金额: $ 10.8万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917926
• 关键词: Adhesions; Affect; Animal Model; Autoimmunity; Binding; Cell Adhesion Molecules; Cell Communication; Cells; Characteristics; Chemotaxis; Chronic; Clinical; Cluster Analysis; DNA Microarray Chip; Development; Disease; Endothelial Cells; Fibroblasts; Funding; Genes; Human; Immune; Immunity; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestinal Mucosa; Intestines; Learning; Ligands; Measures; Mediating; Molecular; Movement; Mucous Membrane; Outcome; Participant; Pathogenesis; Play; Production; Role; Side; Signal Pathway; Signal Transduction; Staging; System; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Tissues; Vascular Endothelial Cell; base; cell motility; cell type; chemokine; chemokine receptor; cytokine; receptor; response; trafficking

DESCRIPTION (provided by applicant): Multiple cell types are involved in the development and persistence of chronic inflammatory response. This also occurs in inflammatory bowel disease (IBD), where long-standing activation of immune and non-immune cells results in severe structural and functional abnormalities. Studies performed during the last funding period have defined the phenotypic and functional characteristics of two types of nonimmune intestinal cells, human intestinal microvascular endothelial cells (HIMEC) and intestinal fibroblasts (HIF), and assessed the interaction between these cells and mucosal T-cells. The results demonstrated that both HIMEC and HIF play an active role in immunity and inflammation through binding of T-cells and cytokine production. These observations strongly support the concept that immune-nonimmune cell interactions are critically involved in the pathogenesis and persistence of IBD. However, the interplay of cells in the mucosa needs to be better understood, particularly in regard to the mechanisms of recruitment of T-cells that stimulate local nonimmune cells. Cell-to-cell communication is controlled by a variety of chemotactic, adhesion and activation molecules that direct movement, contact and stimulation. This proposal will investigate the mechanisms regulating the recruitment of T-cells by HIMEC- and HIF-derived chemokines and the consequences of this effect. The expression of CD40L by activated T-cells and of its counter-receptor CD40 by nonimmune cells is an ideal system to study molecular mechanisms of cell interaction in an integrated fashion. Therefore, we will test the following central hypothesis: The CD40/CD40L system controls a self-perpetuating cycle of T-cell-nonimmune cell interactions that contribute to chronicity of IBD. This hypothesis will be tested by three specific aims: 1) Define the spectrum of T-cell chemokines produced by HIMEC and HIF; 2) Investigate T-cell chemotaxis in response to HIMEC- and HIF-derived chemokines; 3) Identify the receptor-ligand pairs and signaling pathways mediating T-cell-induced HIMEC and HIF chemokine production. Blockade of CD40 or CD40L may interrupt the chronic cycle of immune-nonimmune cell interactions occurring in IBD and result in clinical benefits, as suggested by animal models of autoimmunity and inflammation, including experimental IBD.

描述（由申请人提供）：多种细胞类型涉及 慢性炎症反应的发展和持续。也会出现这种情况 在炎症性肠病（IBD）中，长期激活免疫 非免疫细胞会导致严重的结构和功能异常。 在上一个资助期间进行的研究已经定义了表型 和两种非免疫肠细胞的功能特征， 人肠道微血管内皮细胞（HIMEC）和肠道 成纤维细胞（HIF），并评估这些细胞与粘膜之间的相互作用 T细胞。结果表明HIMEC和HIF均发挥积极作用 通过 T 细胞和细胞因子的结合参与免疫和炎症 生产。这些观察有力地支持了这样的概念： 免疫-非免疫细胞相互作用在发病机制中至关重要 和 IBD 的持续存在。然而，粘膜细胞之间的相互作用需要 更好地理解，特别是在招聘机制方面 刺激局部非免疫细胞的 T 细胞。细胞间的通讯是 由多种趋化分子、粘附分子和活化分子控制 直接的运动、接触和刺激。该提案将调查 HIMEC 和 HIF 衍生的调节 T 细胞募集的机制 趋化因子以及这种效应的后果。 CD40L 的表达 非免疫细胞激活的 T 细胞及其反受体 CD40 是一种 综合研究细胞相互作用分子机制的理想系统 时尚。因此，我们将检验以下中心假设： CD40/CD40L系统控制T细胞-非免疫细胞的自我延续循环 导致 IBD 慢性化的相互作用。这个假设将是 通过三个具体目标进行测试：1) 定义 T 细胞趋化因子的谱 由HIMEC和HIF生产； 2) 研究 T 细胞的趋化性 HIMEC 和 HIF 衍生的趋化因子； 3) 识别受体-配体对并 介导 T 细胞诱导的 HIMEC 和 HIF 趋化因子产生的信号通路。 CD40 或 CD40L 的阻断可能会中断免疫-非免疫的慢性循环 IBD 中发生的细胞相互作用并带来临床益处，如 自身免疫和炎症动物模型表明，包括 实验性炎症性肠病。